title: Dynamics of Aβ42 reduction in plasma, CSF and brain of rats treated with the γ-secretase modulator, GSM-10h.
abstract: BACKGROUND
  Allosteric modulation of γ-secretase is an attractive therapeutic approach for the treatment of Alzheimer's disease. We recently identified a novel γ-secretase modulator, GSM-10h, which effectively lowers Aβ42 production in cells and in amyloid precursor protein transgenic mice.
  
  
  OBJECTIVE
  Here, we describe the in vivo characterization of GSM-10h in a model of endogenous Aβ production.
  
  
  METHODS
  Rats were administered orally with GSM-10h, and the effect on Aβ levels in peripheral and central compartments was determined. In addition, the effect of GSM-10h on Notch processing was assessed.
  
  
  RESULTS
  Acute administration of GSM-10h to rats causes a dose-dependent decrease in the level of Aβ42 in plasma, CSF and brain, with little effect on the level of Aβ40 in these compartments. The magnitude of Aβ42 lowering in the CSF and brain was further enhanced upon sub-chronic administration of GSM-10h. No deleterious effect on Notch processing was evident in either of these studies. To further explore the dynamics of Aβ42 reduction in peripheral and CNS compartments, a time course study was conducted. In all compartments, the decrease in Aβ42 was greatest at 6 h after administration of GSM-10h. This decrease in Aβ42 was maintained for 9-15 h, after which time Aβ42 levels returned to baseline levels. Encouragingly, no rebound in Aβ42 levels beyond baseline levels was observed.
  
  
  CONCLUSIONS
  These findings support the γ-secretase modulator profile of GSM-10h, and highlight the utility of the rat for assessing the pre-clinical efficacy of γ-secretase modulators.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Ltd., New Frontiers Science Park, Harlow, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Hawkins
authors.forename: David C
authors.initials: DC
authors.lastname: Harrison
authors.forename: Sharlin
authors.initials: S
authors.lastname: Ahmed
authors.forename: Robert P
authors.initials: RP
authors.lastname: Davis
authors.forename: Trevor
authors.initials: T
authors.lastname: Chapman
authors.forename: Ian
authors.initials: I
authors.lastname: Marshall
authors.forename: Beverley
authors.initials: B
authors.lastname: Smith
authors.forename: Tania L
authors.initials: TL
authors.lastname: Mead
authors.forename: Andrew
authors.initials: A
authors.lastname: Medhurst
authors.forename: Ged M P
authors.initials: GM
authors.lastname: Giblin
authors.forename: Adrian
authors.initials: A
authors.lastname: Hall
authors.forename: Maria I
authors.initials: MI
authors.lastname: Gonzalez
authors.forename: Jill
authors.initials: J
authors.lastname: Richardson
authors.forename: Ishrut
authors.initials: I
authors.lastname: Hussain
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics; D001923:Brain Chemistry / Q000187:drug effects*; D002452:Cell Count; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects; D000072056:Transcription Factor HES-1
chemical_list: D000085:Acetates; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D051792:Basic Helix-Loop-Helix Proteins; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D010446:Peptide Fragments; D010880:Piperidines; D012333:RNA, Messenger; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C568281:(1-(4-methyl-1-(6-(trifluoromethyl)-3-pyridinyl)pentyl)-2-(4-(trifluoromethyl)phenyl)-4-piperidinyl)acetic acid; C489735:Hes1 protein, rat; C075222:amyloid beta-protein (1-42)